Certain well-known narcotic analgesics belong to the class of 4,5.alpha.-epoxymorphinan compounds which have the following basic ring system in which the atoms are numbered as indicated: ##STR2##
The two most familiar compounds of this class are morphine and its 3-methyl ether, codeine, with the structures indicated below: ##STR3##
When the 6-hydroxyl group of each of these compounds is oxidized to an oxo group, the compounds conveniently are referred to as morphinone and codeinone, respectively. When the N-methyl groups of the latter compounds are replaced by other substituent groups they may be referred to as N-substituted normorphinones and norcodeinones, respectively. There are two types of nomenclature commonly used for describing compounds herein. The trivial names, such s morphine or morphinone, are widely accepted and used for the sake of brevity and clarity. The Chemical Abstracts nomenclature is preferred and is used wherever precision is needed.
The numbering and stereochemical placement of atoms in the morphinan system is depicted in formula I. A dashed line is used to represent a covalent bond projecting below the plane of a reference atom (.alpha.-configuration) while a wedged or heavily accented line signifies a covalent bond above such plane (.beta.-configuration). The serpentine line at the 14-position of formula I is intended to denote the orientation of the covalent bond as being either above or below the plane of reference. The compounds of this invention have the same stereochemical placement of atoms as indicated in the formula I unless otherwise indicated. Another feature of the stereochemistry of the morphinan nucleus is that when the hydrogen in the 14-position is in the .beta.-configuration, the compounds have the same B/C ring junction as the naturally occurring morphine alkaloids and are referred to as B/C cis isomers. Conversely, when the 14-hydrogen atom is in the .alpha.-configuration the compounds are in the B/C trans-configuration and are referred to as isomorphinans.
Morphine and its relatives are used primarily for the relief of pain (i.e., as analgesics). They are narcotic and possess dependence-inducing ability and produce other side effects that make them less than ideal analgesics (emesis, constipation, sweating, respiratory depressions, miosis). A compound with the appropriate profile of analgesic (agonist) and narcotic antagonist actions which is not morphine-like has potential as an analgesic agent for treatment of moderate to severe pain without liability of drug dependence.
Furthermore, a compound having only strong narcotic antagonist action may be a desirable agent for treatment of drug dependence.
Bentley and Hardy disclose in Journal of the American Chemical Society, 89:13, Pp. 3267-73, certain Diels-Alder adducts of thebaine having the formula: ##STR4## where R is methyl or phenyl. It is stated that these compounds possess analgesic activity.
Co-pending application U.S. Ser. No. 215,051 (filed Dec. 10, 1980), now U.S. Pat. No. 4,347,361, discloses 4,5.alpha.-epoxy-3-hydroxy or methoxy-7-(1-hydroxyalkyl or 1-oxoalkyl) morphinan-6-one compounds characterized by the structural formulae: ##STR5##
In the foregoing formulae, R is methyl, propargyl, cyclopropylmethyl, etc. Small et al disclose in U.S. Pat. No. 2,178,010 (issued Oct. 31, 1939) the reaction of dihydrothebaine: ##STR6## with methylmagnesium iodide in refluxing ether solution for 108 hours to give, after workup which includes acid hydrolysis, a mixture from which may be isolated in 45-58% crude yield (15-17.5% rerystallized) methyl dihydrothebainone: ##STR7## and a 9-11% yield (5-6% recrystallized) of isomethyldihydrothebainone: ##STR8##
The introduction of a 7-ketone into the morphinan nucleus with concurrent cleavage of the 4,5 epoxy bond has been reported by Rearick and Gates in Tetrahedron Letters, 507 (1970). They report that treatment of 14-bromocodeinone: ##STR9## with Claisens alkali gives the 7-Keto morphinane. ##STR10## Sawa et al report the preparation of desoxysinomenine characterized by the formula: ##STR11## and desoxydihydrosinomenine characterized by the formula: ##STR12## in Tetrahedron, 15, 144 (1961) from the naturally occurring alkaloid, sinomenine: ##STR13##